Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function

Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function Jingxi Mu, Keiko Maeda, Ayako Ohashi, Takeshi Urano, Yuko Nariai, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3859077/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 May, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted You are reading this latest preprint version Abstract Numerous biological interventions and small molecules are used to treat Crohn’s disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn’s disease. This study aimed to elucidate the expressions of precursor and mature IL-18 in patients with Crohn’s disease who exhibited varied responses to cytokine-targeted treatments, and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expressions of precursor and mature IL-18 and goblet cell function were analyzed in patients. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. Precursor and mature IL-18 expressions were upregulated and goblet cell function was impaired in patients with Crohn’s disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. Therefore, the newly developed monoclonal antibody holds promise as a therapeutic alternative for Crohn’s disease. Health sciences/Gastroenterology Biological sciences/Drug discovery Full Text Additional Declarations Competing interest reported. TU is an employee at Shimane University and is the co-founder and current Chief Medical and Scientific Officer of mAbProtein, a biotechnology company that focuses on the development and commercial use of mAbs in inflammation research, diagnosis, and treatment. The potential conflicts of interest of TU do not alter the authors’ adherence to any of the journal policies on sharing data and materials. The other authors declare no potential conflicts of interest. Supplementary Files IL18supplemetaryfinalSRJM.docx Cite Share Download PDF Status: Published Journal Publication published 06 May, 2024 Read the published version in Digestive Diseases and Sciences → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3859077","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":268001996,"identity":"ac1f673c-222d-4d61-b076-79da6f1eaa0a","order_by":0,"name":"Jingxi Mu","email":"","orcid":"","institution":"Nagoya University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jingxi","middleName":"","lastName":"Mu","suffix":""},{"id":268001997,"identity":"3dea6940-3509-4aa0-9d9f-a16222d2ff91","order_by":1,"name":"Keiko 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TU is an employee at Shimane University and is the co-founder and current Chief Medical and Scientific Officer of mAbProtein, a biotechnology company that focuses on the development and commercial use of mAbs in inflammation research, diagnosis, and treatment. The potential conflicts of interest of TU do not alter the authors’ adherence to any of the journal policies on sharing data and materials. The other authors declare no potential conflicts of interest.","formattedTitle":"Monoclonal Antibodies Against Mature Interleukin-18 Ameliorate Colitis and Repair Goblet Cell Function","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3859077/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3859077/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Numerous biological interventions and small molecules are used to treat Crohn’s disease; however, the effectiveness of these treatments varies largely. Non-responsiveness to biological therapies is associated with interleukin (IL)-18 gene polymorphisms and high IL-18 expression has been implicated in the pathogenesis of Crohn’s disease. This study aimed to elucidate the expressions of precursor and mature IL-18 in patients with Crohn’s disease who exhibited varied responses to cytokine-targeted treatments, and determine whether selective inhibition of mature IL-18 offers a novel therapeutic avenue. We generated a monoclonal antibody that specifically recognizes the neoepitope of caspase-cleaved mature IL-18. Expressions of precursor and mature IL-18 and goblet cell function were analyzed in patients. Anti-mature IL-18 monoclonal antibodies were intraperitoneally administered in acute colitis mouse model, and the disease activity index, body weight loss, tissue pathology, proinflammatory cytokine expression, goblet cell function, and microbiota composition were assessed. Precursor and mature IL-18 expressions were upregulated and goblet cell function was impaired in patients with Crohn’s disease who were unresponsive to biological therapies. Administration of anti-mature IL-18 antibodies ameliorated induced colitis by repairing goblet cell function and restoring the mucus layer. 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